The long term objective of this proposal is to gain insight into the mechanisms of resistance and tolerance to infectious agents in man. Leprosy, caused by the intracellular pathogen M. leprae, presents as a clinical/immunologic spectrum, providing an attractive model for investigating the regulation of immune responses to infection. In the eight years of funding for this grant, we have developed immunologic and molecular strategies for investigating the immune response in lesions of disease. We propose to use these approaches to further define mechanisms of immunity and immunosuppression in leprosy. The objectives are the following: 1) to identify alpha-beta T-cell populations which are overrepresented in leprosy lesions according to dominant T-cell receptors; 2) to elucidate immunodominant antigens using T-cells bearing predominant TCRs, including the antigen recognized by V-beta6 T-cells and the V-beta8 superantigen; 3) to define the functional roles of T-cells in leprosy lesions according to cytokine pattern, and; 4) to determine the factors which bias the cytokine response. The information gained from these studies of CD4+ and CD8+ a- T-cells, along with concomitant studies in our lab of gamma-delta T-cells, will improve our understanding of leprosy and, in general contribute to our knowledge concerning human immune responses to infection.